Abstract:

Systems, devices, and methods for transdermal delivery of one or more
therapeutic active agents to a biological interface. A transdermal drug
delivery system is provided for passive transdermal delivery of one or
more ionizable active agents to a biological interface of a subject. A
transdermal drug delivery system includes a backing substrate, and an
active agent layer. The active layer includes a thickening agent, a
plasticizer, and a therapeutically effective amount of an ionizable
active agent.

Claims:

1. A passive transdermal delivery device comprising:a backing substrate;
andan active agent layer, wherein the active agent layer is substantially
anhydrous and oil-free and includes a thickening agent and an ionizable
active agent, and wherein the ionizable active agent is electrically
neutral in the active agent layer and dissociates into an ionized active
agent upon contacting an aqueous medium.

2. The passive transdermal delivery device of claim 1 wherein the
ionizable active agent is a salt of an amine-containing active agent.

3. The passive transdermal delivery device of claim 2 further comprising a
humectant.

4. The passive transdermal delivery device of claim 2 wherein the
thickening agent is HPC, the ionizable active agent is Procaterol HCl and
the humectant is urea.

24. A method of treating a condition associated with an obstructive
respiratory ailment in a subject comprising:applying to the subject's
skin a passive transdermal delivery device comprising: a backing
substrate; and an active agent layer, wherein the active agent layer is
substantially anhydrous and oil-free and includes a thickening agent and
an ionizable active agent, and wherein the ionizable active agent is
electrically neutral in the active agent layer and dissociates into an
ionized active agent upon contacting an aqueous medium; andallowing the
ionizable active agent to dissociate into the ionized active agent.

25. The method of claim 24 comprising contacting the ionizable active
agent to sweat of the subject's skin to produce the ionized active agent.

[0003]This disclosure generally relates to the field of topical and
transdermal administration of active agents and, more particularly, to
systems, devices, and methods for transdermally delivering active agents
to a biological interface via passive diffusion.

[0004]2. Description of the Related Art

[0005]Conventionally administered active agents in the form of, for
example, capsules, injectables, ointments, and pills are typically
introduced into the body as pulses that usually produce large
fluctuations of active agent concentrations in the bloodstream and
tissues and, consequently, provide unfavorable patterns of efficacy and
toxicity. For example, conventionally administered active agents for
obstructive respiratory aliment treatments generally include inhalation
aerosols and inhalation solutions typically administered using inhaler
devices (e.g., inhalers). Typically, inhaler devices have an active
agent, medication, or drug stored in solution, in a pressurized canister,
which is attached to a manually actuated pump. To use a standard inhaler
device, a user must first exhale, then insert a mouth-piece end of the
inhaler device in their mouth, then manually actuate the pump of the
inhaler device while retaining the mouth-piece end in their mouth, and
then the user may have to hold their breath for a prerequisite amount of
time so that the active agent or medication or drug has a chance to be
absorbed into the body instead of being exhaled from the user. Some users
may find inhaler devices difficult to use. For example, a user of an
inhaler device needs the ability to physically manipulate and actuate the
inhaler device. Young users or feeble users may have difficulty mustering
the coordination necessary to properly use an inhaler device.
Additionally, users lacking the ability to hold their breath for the
prerequisite time may likewise be unable to take advantage of inhaler
devices.

[0007]Skin, the largest organ of the human body, offers a painless and
compliant interface for systemic drug administration. As compared with
injections and oral delivery routes, transdermal drug delivery increases
patient compliance, avoids metabolism by the liver, and provides
sustained and controlled delivery over long time periods. Transdermal
delivery may in some instances, increase the therapeutic value by
obviating specific problems associate with an active agent such as, for
example, gastrointestinal irritation, low absorption, decomposition due
to first-pass effect (or first-pass metabolism or hepatic effect),
formation of metabolites that cause side effects, and short half-life
necessitating frequent dosing.

[0008]Although skin is one of the most extensive and readily accessible
organs, it is relatively thick and structurally complex. Thus, it has
historically been difficult to deliver certain active agents
transdermally. To transport through intact skin into the blood stream or
lymph channels, the active agent must penetrate multiple and complex
layers of tissues, including the stratum corneum (i.e., the outermost
layer of the epidermis), the viable epidermis, the papillary dermis, and
the capillary walls. It is generally believed that the stratum corneum,
which consists of flattened cells embedded in a matrix of lipids,
presents the primary barrier to absorption of topical compositions or
transdermally administered drugs.

[0009]Due to the lipophilicity of the skin, water-soluble or hydrophilic
drugs are expected to diffuse more slowly than lipophilic drugs. While
lipid-based permeation enhancers (such as hydrophobic organic substances
including vegetable oils) can sometimes improve the rate of diffusion,
such permeation enhancers do not mix well with hydrophilic drugs. For
example, development of a transdermal vehicle for delivery of Procaterol,
a bronchial dilator, has faced numerous difficulties. Procaterol is
highly hydrophilic, and delivery through the skin has not been possible
when combined with hydrophobic organic substances.

[0010]Commercial acceptance of transdermal delivery devices or
pharmaceutically acceptable vehicles is dependent on a variety of factors
including cost to manufacture, shelf life, stability during storage,
efficiency and/or timeliness of active agent delivery, biological
capability, and/or disposal issues. Commercial acceptance of transdermal
delivery devices or pharmaceutically acceptable vehicles is also
dependent on their versatility and ease-of-use.

[0011]The present disclosure is directed to overcoming one or more of the
shortcomings set forth above, and/or providing further related
advantages.

BRIEF SUMMARY

[0012]Transdermal delivery devices and topical formulations are described.
In various embodiments, ionizable and ionized active agents can passively
permeate through skin to reach the blood stream and ultimately be
delivered systemically.

[0013]One embodiment describes a passive transdermal delivery device
comprising: a backing substrate; and an active agent layer, wherein the
active agent layer is substantially anhydrous and oil-free and includes a
thickening agent and an ionizable active agent, and wherein the ionizable
active agent is electrically neutral in the active agent layer and
dissociates into an ionized active agent upon contacting an aqueous
medium.

[0014]A further embodiment describes a topical formulation comprising: a
thickening agent, an ionized active agent; and an aqueous medium, wherein
the topical formulation is substantially oil-free.

[0015]Yet another embodiment describes a method of treating a condition
associated with an obstructive respiratory ailment in a subject
comprising: applying to the subject's skin a passive transdermal delivery
device comprising: a backing substrate; and an active agent layer,
wherein the active agent layer is substantially anhydrous and oil-free
and includes a thickening agent and an ionizable active agent, and
wherein the ionizable active agent is electrically neutral in the active
agent layer and dissociates into an ionized active agent upon contacting
an aqueous medium; and allowing the ionizable active agent to dissociate
into the ionized active agent.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0016]In the drawings, identical reference numbers identify similar
elements or acts. The sizes and relative positions of elements in the
drawings are not necessarily drawn to scale. For example, the shapes of
various elements and angles are not drawn to scale, and some of these
elements are arbitrarily enlarged and positioned to improve drawing
legibility. Further, the particular shapes of the elements, as drawn, are
not intended to convey any information regarding the actual shape of the
particular elements, and have been solely selected for ease of
recognition in the drawings.

[0017]FIG. 1 is an isometric view of an active side of a transdermal drug
delivery device according to one illustrated embodiment.

[0018]FIG. 2A is a plan view of the active side of the transdermal
delivery device of FIG. 1 according to one illustrated embodiment.

[0019]FIG. 2B is an exploded view of the transdermal delivery device of
FIG. 1 according to one illustrated embodiment.

[0020]FIG. 3 is an isometric view of a bottom side of an active side of a
transdermal delivery device according to one illustrated embodiment.

[0021]FIG. 4A is a plan view of the active side of a transdermal delivery
device according to one illustrated embodiment.

[0022]FIG. 4B is an exploded view a transdermal delivery device according
to one illustrated embodiment.

[0039]FIG. 21 is a flow diagram of an exemplary method for manufacturing a
transdermal drug delivery device according to one illustrated embodiment.

[0040]FIGS. 22A-22C show a spin-coating process according to one
illustrated embodiment.

[0041]FIG. 23A is a Dynamic Light Scattering measurement plot of Frequency
versus Particle Size according to one illustrated embodiment.

[0042]FIG. 23B is a cross sectional view of an active agent layer
illustrating the interactions of HPC and Procaterol HCl according to one
illustrated embodiment.

[0043]FIG. 24 is a flow diagram of an exemplary method of preventing or
treating a condition associated with an obstructive respiratory ailment
according to one illustrated embodiment.

[0044]FIG. 25A is an exploded view of a test diffusion cell for evaluating
in vitro transdermal permeation according to one illustrated embodiment.

[0045]FIGS. 25B and 25C show an exploded and an unexploded view of a Franz
test diffusion cell for evaluating in vitro transdermal permeation
according to one illustrated embodiment.

[0046]FIG. 26 is a plot of Procaterol HCl Delivered versus Time according
to one illustrated embodiment.

[0047]FIG. 27 is an exemplary permeation profile of Procaterol to a
Phosphate Buffered Saline (PBS) versus Time plot according to one
illustrated embodiment.

[0048]FIG. 28 is a plot of permeation profile of Procaterol to a Phosphate
Buffered Saline (PBS) versus Time for an exemplary embodiment of a
delivery device.

[0049]FIG. 29 is plot of permeation profile of Procaterol to a Phosphate
Buffered Saline (PBS) versus Time for an exemplary embodiment of a
delivery device.

[0050]FIG. 30 is a plot of permeation profile of Procaterol to a Phosphate
Buffered Saline (PBS) versus Time for an exemplary embodiment of a
delivery device.

[0051]FIG. 31 is a plot of permeation profile of Procaterol to a Phosphate
Buffered Saline (PBS) versus Time for an exemplary embodiment of a
delivery device.

[0052]FIG. 32 is a plot of permeation profile of Procaterol to a Phosphate
Buffered Saline (PBS) versus Time for an exemplary embodiment of a
delivery device.

DETAILED DESCRIPTION

[0053]In the following description, certain specific details are included
to provide a thorough understanding of various disclosed embodiments. One
skilled in the relevant art, however, will recognize that embodiments may
be practiced without one or more of these specific details, or with other
methods, components, materials, etc. In other instances, well-known
structures associated with delivery devices including, but not limited
to, protective coverings and/or liners to protect delivery devices during
shipping and storage have not been shown or described in detail to avoid
unnecessarily obscuring descriptions of the embodiments.

[0054]Unless the context requires otherwise, throughout the specification
and claims which follow, the word "comprise" and variations thereof, such
as, "comprises" and "comprising" are to be construed in an open,
inclusive sense, that is as "including, but not limited to."

[0055]Reference throughout this specification to "one embodiment," or "an
embodiment," or "in another embodiment," or "in some embodiments" means
that a particular referent feature, structure, or characteristic
described in connection with the embodiment is included in at least one
embodiment. Thus, the appearance of the phrases "in one embodiment," or
"in an embodiment" or "in another embodiment," or "in some embodiments"
in various places throughout this specification are not necessarily all
referring to the same embodiment. Furthermore, the particular features,
structures, or characteristics may be combined in any suitable manner in
one or more embodiments.

[0056]It should be noted that, as used in this specification and the
appended claims, the singular forms "a," "an," and "the" include plural
referents unless the content clearly dictates otherwise. Thus, for
example, reference to an active agent includes a single active agent, or
two or more active agents. It should also be noted that the term "or" is
generally employed in its sense including "and/or" unless the content
clearly dictates otherwise.

[0057]It is conventionally believed that ionic drugs do not easily
permeate through the skin and are generally not suited for topical
formulations (e.g., creams and lotions) or transdermal patches. However,
according to the various embodiments described herein, certain ionizable
active agents are capable of permeating skin and entering into blood
stream or lymph channels. Based on both theoretical models and empirical
results of ion permeation within the skin, it is described herein a
logical approach to designing transdermal delivery devices (e.g.,
patches) and topical formulations to passively deliver an ionized active
agent. Also described are methods of making and using the same.

Transdermal Delivery Device

[0058]One embodiment provides a passive transdermal delivery device, such
as a transdermal patch, comprising a backing substrate and an active
agent layer, wherein the active agent layer is substantially anhydrous
and oil-free and includes a thickening agent and an ionizable active
agent, and wherein the ionizable active agent is electrically neutral in
the active agent layer and dissociates into an ionized active agent upon
contacting an aqueous medium.

[0059]As used herein, "transdermal delivery" refers to passive diffusion
of ionic active agents in the absence of externally-applied electrical
current. However, as a result of diffusion through skin, the ionic
substances establish a concentration gradient, which can give rise to an
electrical potential difference on either side of the skin. The
electrical potential difference may speed up or hamper the ionic
diffusion process, depending on a host of interrelating factors,
including the velocity, flux and size of the various ions. It is
discussed herein that ionic passive diffusion under controlled conditions
can benefit from the dual effects of the electrical potential as well as
the concentration gradient.

[0060]FIGS. 1, 2A, and 2B show a first exemplary embodiment of a delivery
device 10a. In some embodiments, the delivery device 10a is configured to
transdermally deliver one or more therapeutic active agents to a
biological interface of a subject via passive diffusion. As used herein,
"biological interface" refers to both skin and mucosal membrane (such as
nasal membrane). Unless specified otherwise, all descriptions regarding
skin permeation also apply to mucosal membranes. The delivery device 10a
includes a backing substrate 12a having opposed sides 13a and 15a. An
optional base layer 14a is disposed and/or formed on the side 13a of the
backing substrate 12a. An active agent layer 16a is disposed and/or
formed on the base layer 14a. The backing substrate 12a, the optional
base layer 14a, and the active agent layer 16a may be formed from pliable
materials such that the delivery device 10a will conform to the contours
of the subject.

[0061]FIG. 1 shows an isometric view of the delivery device 10a. When the
delivery device 10a is placed on a subject (not shown), the active agent
layer 16a is proximal to the subject and the backing substrate 12a is
distal to the subject. The backing substrate 12a may include an adhesive
such that the delivery device 10a may be applied to the subject and be
adhered thereon. In some embodiments, the backing 12a encases the
delivery device 10a. Non-limiting examples of backing substrates include
3M® CoTran® Backings, 3M® CoTran® Nonwoven Backings, and
3M® Scotchpak® Backings.

[0062]The optional base layer 14a may be constructed out of any suitable
material including, for example, polymers, thermoplastic polymer resins
(e.g., poly(ethylene terephthalate)), and the like. In some embodiments,
the optional base layer 14a and the active agent layer 16a may cover a
substantial portion of the backing substrate 12a. For example, in some
embodiments, the backing substrate 12a, the optional base layer 14a, and
the active agent layer 16a may be disk shaped and the backing substrate
12a may have a diameter of approximately 15 millimeter (mm) and the
optional base layer 14a and the active agent layer 16a may have
respective diameters of approximately 12 mm. In some embodiments, the
sizes of the backing substrate 12a, the base layer 14a, and the active
agent layer 16a may be larger or smaller, and in some embodiments, the
relative size differences between the backing substrate 12a, the base
layer 14a, and the active agent layer 16a may be different from that
shown in FIGS. 1, 2A, and 2B. In some embodiments, the size of the active
agent layer 16a may depend upon, among other things, the active agent or
active agents being delivered by the delivery device 10a and/or the rate
at which the active agent or active agents are to be delivered by the
delivery device 10a. Typically, the backing substrate 12a and the base
layer 14a are sized to the active agent layer 16a such that the sizes of
the backing substrate 12a and the base layer 14a are least the size of
the active agent layer 16a.

[0063]FIG. 3 shows a second embodiment of a delivery device 10b. In this
embodiment, the elements and features labeled with a reference numeral
and the letter "b" corresponds to features and components that are
similar at least in some respects as those of FIGS. 1, 2A, and 2B that
are labeled with the same reference numeral and the letter "a". This
embodiment may be effective in enhancing the delivery of an active agent
in instances including, but not limited to, where the active agent has
unfavorable dissolving kinetics and may also be employed in instances
where the dissolving kinetics of the active agent are not unfavorable.

[0064]The delivery device 10b includes, a backing substrate 12b, a base
layer 14b, and an active agent layer 16b storing one or more ionizable
active agents. It has been found that replenishing the ionizable active
agent in the active layer 16b may play an important roll for proper
delivery of the active agent. In particular, by replenishing the
ionizable active agent in the active agent layer 16b (or 16a), it is
possible to maintain a concentration of the ionizable active agent in the
active agent layer 16b (or 16a) that is fairly or substantially constant
over time. Accordingly, in the embodiment illustrated in FIG. 3, the
delivery device 10b may include an inner active agent-replenishing layer
18b' and an outer active agent-replenishing layer 18b''. The active
agent-replenishing layers 18b', 18b'' may be formed from a material
(e.g., a thickening agent) such as, but not limited to, hydroxypropyl
cellulose (HPC). The active agent-replenishing layers 18b', 18b'' cache
additional ionizable active agents that diffuse into the active agent
layer 16b.

[0065]FIGS. 4A and 4B show a third embodiment of a delivery device 10c. In
this embodiment, the elements and features labeled with a reference
numeral and the letter "c" corresponds to features and components that
are similar at least in some respects as those of FIGS. 3A and 3B that
are labeled with the same reference numeral and the letter "b". The
delivery device 10c includes an outer active agent-replenishing layer 18c
interposing the active agent layer 16c and the base layer 14c. In some
embodiments, an active agent-replenishing layer 18c may be disposed on
the active agent layer 16c distal from the base layer 14c such that the
active agent layer 16c interposes the agent-replenishing layer 18c and
the base layer 14c.

[0066]In various embodiments, the active agent layer 16a includes a
thickening agent and a therapeutically effective amount of an ionizable
active agent.

A. Thickening Agent:

[0067]Thickening agent" refers to an inert and viscous material that
provides the bulk of the active agent layer. For example, the thickening
agent provides a sol into which the active agent is dispersed. By
adjusting the relative amounts of the thickening agent and the active
agent, active agent layers of selected concentrations and viscosities can
be prepared. Typically, the thickening agent is a cellulose derivative.
Exemplary thickening agents include, but are not limited to,
polysaccharides (e.g., hydroxypropyl cellulose, hydroxymethyl cellulose,
hydroxypropyl methylcellulose and the like) proteins, viscosity
enhancers, and the like.

B. Ionizable Active Agent:

[0068]Active agent" refers to a compound, molecule, or treatment that
elicits a biological response from any host, animal, vertebrate, or
invertebrate, including, but not limited to, fish, mammals, amphibians,
reptiles, birds, and humans. Non-limiting examples of an active agent
includes a therapeutic agent, a pharmaceutical agent, a pharmaceutical
(e.g., a drug, a therapeutic compound, a pharmaceutical salt, and the
like), a non-pharmaceutical (e.g., a cosmetic substance, and the like), a
vaccine, an immunological agent, a local or general anesthetic or
painkiller, an antigen or a protein or peptide such as insulin, a
chemotherapy agent, and an anti-tumor agent.

[0069]An ionizable active agent refers to an active agent, as defined
herein, that is electrically neutral (i.e., non-ionized) prior to
contacting an aqueous medium. Upon contacting an aqueous medium, the
ionizable active agent dissociates into an "ionized active agent" and a
counterion. Depending on the chemical structure of the ionizable active
agent, the ionized active agent can be cationic or anionic. As used
herein, an aqueous medium refers to a water-containing environment,
including moisture, aqueous solution (e.g., saline solution), and sweat
present on skin.

[0070]Typically, the ionizable active agent is a salt. In certain
embodiments, an active agent containing one or more amines (including
primary, secondary and tertiary amine) or imines can be converted into an
ionizable salt form in the presence of an acid. Preferably, the active
agent has a tertiary amine or secondary amine and the acid is a strong
acid such as hydrochloride acid (HCl). The salt dissociates into a
cationic active agent (containing a positively-charged ammonium ion) and
a counter ion (e.g., chloride). Thus, the acid (organic or inorganic) is
selected such that the counter ion is physiologically compatible.
Exemplary acids include, for example, phosphoric acid (phosphate
counterion), citric acid (citrate counterion), acetic acid (acetate
counterion), lactic acid (lactate counterion) and so forth.

[0071]Thus, in certain embodiments, the ionizable active agent that
produces a cationic active agent is an amine-containing drug. In one
embodiment, the active agent layer includes Procaterol as a
pharmaceutically acceptable salt, i.e.,
8-hydroxy-5-[1-hydroxy-2-[(1-methylethyl)amino]butyl]-2(1H)-quinolinone,
[(R*,S*)-(+-)-8-hydroxy-5-(1-hydroxy-2-((1-methylethyl)amino)butyl)-2(1H)-
-quinolinone] as a pharmaceutically acceptable salt. See, e.g., U.S. Pat.
No. 4,026,897 which is hereby incorporated by reference in its entirety.
Suitable salt forms of Procaterol include Procaterol HCl and its hydrate
forms, including Procaterol HCl hemihydrate, Procaterol HCl hydrate, and
respective isomers thereof:

[0074]In other embodiments, the ionizable active agent contains one or
more carboxylic acids (--COOH), which can be in a salt form. This type of
ionizable active agent dissociates into anionic active agent and a
physiologically compatible counterion. For example, in certain
embodiments, the ionizable active agent is an alkaline salt of
Diclofenac. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID).
The sodium salt of Diclofenac (i.e., monosodium
2-(2-(2,6-dichlorophenylamino)phenyl)acetate) has the following general
molecular formula:

Other suitable physiologically-compatible counterions include, for
example, ammonium, potassium and so forth.

[0075]In other embodiments, the ionizable active agent is a salt of
ascorbic acid or a derivative thereof. Ascorbic acid is an antioxidant
and inhibits melanogenesis. Its salt form can dissociate into ascorbate
anion and a positively charged counterion. For example, the sodium salt
of ascorbic acid (or sodium ascorbate in L or D form) is shown below:

[0076]In some instances, once permeate into the skin, ionized active
agents can rapidly depart from the lipophilic bilayers in the skin and
reach deeper into the tissue, and ultimately reach the blood stream and
deliver systemically.

[0077]Polarizable active agents are also within the scope of suitable
active agents. "Polarizable active agent" is also electrically neutral
but exhibits more polarity at one portion relative to another portion in
the presence of a polar solvent (such as an aqueous medium, as defined
herein).

C. Optional Components

[0078]In addition to the thickening agent and the ionizable active agent,
the active agent layer 16a may further include one or more optional
components such as an ionizable additive, a humectant, a plasticizer and
a permeation enhancer.

[0079]Ionizable additive" refers to an inert salt that produces ions upon
contact with an aqueous medium. As discussed in more detail herein, the
ionizable additive dissociated ions that contribute to the formation of
concentration gradient and influence the electrical potential induced by
ion flux during the ionic permeation process. Advantageously, based on
their permeation characteristics, suitable ionizable additive can be
selected to aid the permeation process of the ionized active agent.
Exemplary ionizable additives include potassium chloride (KCl), sodium
chloride (NaCl), and the like.

[0080]In some embodiments, the active agent layer 16a may include a
humectant. Exemplary humectants include, but are not limited to,
hygroscopic substances, molecules having several hydrophilic groups
(e.g., hydroxyl groups, amines groups, carboxyl groups, esterified
carboxyl groups, and the like), compounds having an affinity to form
hydrogen bonds with water molecules, and the like. Further examples of
humectants include, but are not limited to, urea, glycerine, propylene
glycol (E 1520) and glyceryl triacetate (E1518), polyols (e.g., sorbitol
(E420), xylitol and maltitol (E965), polymeric polyols (e.g.,
polydextrose (E1200), natural extracts (e.g., quillaia (E999), and the
like.

[0081]In some embodiments, the active agent layer 16a may include a
plasticizer. The term "plasticizer" or "softener" typically refers to a
substance, compound, or mixture that is added to increase the flexibility
of the thickening agent. Suitable plasticizers include polyglycols
polyglycerols, polyols, polyethylene glycols (PEG, polyethylene glycols
(e.g., PEG-200, PEG-300, PEG-400, PEG-4000, PEG-6000),
di(2-ethylhexyl)phthalate (DEHP), triethylene glycol, and the like.

[0082]In some embodiments, combining a one or more organic components with
an active agent may promote or enhance absorption of the active agent
into the skin. For example, surfactants may alter protein structure or
fluidize skin and increase permeation. In some embodiments, absorption of
ionic or polar active agents may be enhanced by including surfactants
with hydrophilic head groups. A lipophilic portion of the surfactant may
assist the permeation through skin.

[0084]In certain embodiments, the active agent layer is substantially
anhydrous and oil-free. It is considered "substantially anhydrous" when
the active agent layer contains no more than 5% by weight of water, and
more typically, no more than 3%, 2%, 1% or 0.5% of water. Under the
substantially anhydrous condition, the ionizable active agent remains
electrical neutral, which is generally more stable than its ionized form.
Thus, longer shelf-life of the active agent can be expected. It is
consider "substantially oil-free" when the active agent layer contains no
more than 5% by weight of a lipophilic component such as fatty acids,
vegetable oil, petroleum or mineral oil, including short chain (e.g.,
fewer than 14 carbons) saturated hydrocarbons, silicone oils and the
like. These conventional permeation enhancers are not necessary to
provide assistance to ionic permeation. On the other hand, because oil
tends to destabilize the ionizable or ionized active agent during storage
or delivery, an oil-free active agent layer is expected to provide
long-term stability to the active agent.

[0085]In various embodiments, the amount of ionizable active agent in the
active agent layer depends on both its permeation rate and dosage
regimen. In addition, the concentration of the ionizable active agent in
the active agent layer 16a is selected dependent on factors such as, but
not limited to, the solubility of the ionized active agent, the rate of
solution of the ionizable active agent, and so forth.

[0086]The initial loading of the ionizable active agent also influences
the permeation of the ionized active agent. Higher concentration of the
ionizable active agent can lead to higher permeation rate. Thus, it is
desirable to load maximum amount of the active agent within a minimum
amount of the thickening agent (i.e., forming the highest concentration
of active agent in a thinnest active agent layer). On the other hand,
because the active agent is not typically fully absorbed by the skin,
care should be taken to limit the initial loading level to ensure that
even at a full dose, the patch is not lethal if ingested. For example, a
Procaterol HCl patch typically contains about 25 μg to maximally 100
μg Procaterol HCl.

[0087]Typically, the active agent layer may include from about 0.001 wt %
to about 10 wt % of an ionizable active agent, more typically, the active
agent layer may include from about 0.01 wt % to 5 wt %, or from about
0.01 wt % to 0.1 wt %, 0.1 wt % to 1 wt %, 0.1 wt % to 5 wt % of the an
ionizable active agent.

[0088]In certain embodiments, the active agent layer comprises HPC and
Procaterol HCl. In a more specific embodiment, the active agent layer
comprises HPC, Procaterol HCl and urea. In other embodiments, the active
agent layer comprises HPC, Procaterol HCl, and glycerol. In other
embodiments, the active agent layer comprises HPC, Lidocaine HCl, and
glycerol. In other embodiments, the active agent layer comprises HPC and
Sodium Diclofenc. In other embodiments, the active agent layer comprises
HPC and AA2-G.

[0089]In other embodiments, the active agent layer consists essentially of
a thickening agent, an ionizable active agent and a humectant. In a
particular embodiment, the active agent layer consists essentially of
HPC, Procaterol HCl and urea.

E. Theoretical Model and Empirical Results of Ion Permeation

[0090]As discussed, a variety of ionizable active agents are capable of
dissociating into ions that transport through the skin. When analyzing
the transdermal delivery of an ionic substance into the skin, simple
diffusion based upon a concentration gradient cannot provide a complete
picture of the events that take place. Without being bound by the
following theories, an analysis is provided herein to explain the ionic
transdermal mechanism based on electric potential in addition to
concentration gradients. It is believed that the driving force for ion
transport through a membrane (e.g., skin) relates to both concentration
gradients and electric potential gradients induced by the ionic flux. As
used herein, "flux" or "ionic flux" refers to the rate of an ionic
substance (i.e., ionized active agent) that moves across a unit area.
Typically, ionic flux is represented by, e.g., μg cm-2h-1 or
mol cm-2h-1.

[0092]The first term in Eq. 1, often used in analyzing electrochemical
systems, relates to ion diffusion while the second term relates to ion
movement due to an electric field. FIG. 5 schematically illustrate ionic
flux-induced electrical field. As shown, a high concentration of ionic
drug solution is placed in the left side chamber 20. A porous membrane 22
corresponding to the surface of the skin is connected to the chamber 20,
and the ionic drug solution contacts the porous membrane at a position
x=0. The initial concentration of the drug solution is C0. The
thickness of the porous membrane is d, and the concentration of the ionic
drug in the chamber 24 to the right of the porous membrane is taken as
Cd. Diffusion proceeds from the left side chamber 20 toward the
right side of the system in FIG. 5, and establishes a concentration
gradient, which induces an electrical potential difference.

[0093]When cations and anions move through the skin, their velocities are
defined in Eq. 2.

v + = - Π + RT ln ln c x
v - = - Π - RT ln ln c x
Eq . 2

[0094]In Eq. 2, ω.sub.+ and ω.sub.- represent the molar
mobility of cations and anions, respectively, in solution. Cations and
anions move independently in solution and in the membrane, but both move
according to the same concentration gradient. The relative speeds of
anions and cations thus depend only upon Eq. 2. Chemical compounds
employed as drugs or cosmetics are often chloride or alkali metal salts
of organic substances, meaning that once dissociated into ions, one ion
(generally the active agent ion) is much larger than the other.
Consequently, the overall size of the drug ion does not change
significantly after dissociation, and it is reasonable to expect that the
transdermal delivery of the ionic drug due to diffusion (based on
concentration gradient) should not differ significantly from that of the
neutral molecule.

[0095]FIG. 6 shows ion movements over time (Δt) when the cation
velocity is assumed to be half of that of anions. Cations (27a) move for
v+Δt (26a) while anions (27b) move v-Δt (26b). A charge
separated state is thus generated in the membrane, leading to an electric
potential difference over a very short distance. This electric potential
difference will help accelerate cation movement, while slowing anion
movement. Eq. 3 describes this effect, which is not seen in the movement
of neutral molecules, mathematically. In Eq. 3, Anions and cations move
in opposite directions as shown in Eq. 3. Cations are represented using
+, while anions are represented using -. Over time both anions and
cations move from one side of the membrane to the other, maintaining
electro-neutrality.

[0096]Eq. 4 shows the relationship between the velocity (v) and flux (J)
of the ions. The concentration of the ions (c.sub.+ and c.sub.-) are
identical if the drug being examined consists of monovalent cations and
anions, and the velocity of the cation should be the same as that of the
anion.

[0098]A relationship between the concentration gradient and the electric
potential gradient is thus obtained. Integrating Eq. 5 from 0 to d and
from c0 to cd leads to an expression showing the electric
potential difference (Δφ=dφ/dx) through the membrane.

[0100]At steady state, it is believed that the ion flux is given by the
same equation for anions and cations. Diffusion of both ions occurs
depending upon the concentration gradient when a drug permeates as
dissociated ions, represented by dc/dx and the diffusion coefficient of
Eq. 8.

D = 2 Π + Π - Π + + Π - RT
Eq . 8

[0101]Further, it is necessary to linearly approximate the concentration
gradient or the electric potential gradient to solve equation 9. This
leads to equation 10. Integrate equation 10 over C0 to Cd after
values for x, 0 to d, and c are obtained. This solves for the flux J, as
shown in Eq. 11, which is the so-called Goldman equation.

[0102]The potential difference across the skin has been considered for a
single component system. In practice, a variety of ionic compounds may be
present (including, for example, ionized active agent and ionized
additive). Eq. 12 shows a relationship used for multi-component systems.

[0103]Thus, a film potential can be calculated provided that the ion
mobility (omega) and concentration (c) within the skin are known. The ion
transport speed can then be found from the calculated film potential.

[0104]As shown above, movement of ions across or within the skin cannot be
viewed in a simple diffusion model because the generation of a membrane
potential further influences the concentration gradient. It is therefore
necessary to experimentally evaluate this phenomenon and effectively use
the results in drug product development. It is also desirable to evaluate
potential additives based on this theory.

[0105]An H-shaped Franz cell (FIG. 7) was used to evaluate the theory
described herein. As shown, the Franz cell 28 includes a donor chamber
30a and a receiver chamber 30b. The donor chamber 30a contains an ionic
active agent, which permeates through a membrane 32 to reach the receiver
chamber 30b. A working electrode 34a was inserted in the donor chamber
30a, while a counter electrode 34b (i.e., reference electrode) was
inserted in the receptor chamber 30b. It is possible to measure the
electrical potential difference induced by the ionic diffusion/permeation
and the concentration gradient thus established.

[0106]FIGS. 8A-8C illustrate how electrical potential differences
influence ionic movement. As shown, depending on the charges of the ionic
active agent (cationic or anionic), its movement can be affected by the
electrically potential difference established across the skin. FIGS.
8A-8C further illustrate that, by selecting certain ionizable additive
with known permeation characteristics, it is possible to further
accelerate the ionic permeation or at least ameliorate an unfavorable
condition by canceling out the electrical potential that retards the
movement of the ionic drug.

[0107]FIG. 8A shows that an electrical potential difference is generated
on either side of the skin 36. When the electrical potential is lower on
the inside of the skin (contacting the body 38), cation movement is
accelerated by the potential difference, while the anion movement is
suppressed. Thus, for cationic active agent, it is desirable that a large
membrane potential be generated by an ionized additive. For example, an
additive dissociates into easily permeable anions and difficult to
permeate cations is preferable.

[0108]FIG. 8B shows that an electrical potential difference is generated
that favors the anion movement while suppressing the cation movement.
Thus, if a cationic active agent is to be delivered, it is preferable
that an ionized additive is present to cancel out the potential
difference that slows down the cation movement.

[0109]FIG. 8C shows that no electrical potential difference is generated.
Thus, it is preferable to include an ionized additive that dissociates
into easily permeable cations and difficult to permeate anions so as to
create an electrical potential difference that favors cation movement.

[0110]For anionic active agent, the impacts of the electrical potential
difference should be reversed as those of the cationic active agent.
Thus, in the condition described in FIG. 8A, an additive that dissociates
into easily permeable cations and difficult to permeate anions is
preferable. In FIG. 8B, it is preferable that the ionized additive
cancels out the generated potential difference. For example, an effective
additive will have similar permeation speeds within the skin between its
dissociated cations and anions. For FIG. 8C, an additive that dissociates
into easily permeable anions and difficult to permeate anions is
preferable.

[0111]As shown, the mobility of ions within the skin can be influenced by
the components (e.g., ionizable additive) contained in the drug product
if those components also permeate into the skin. Enhancers used in the
conventional patches can be used to improve the speed of the drug ions as
long as the enhancers are not adversely influenced by the electric
potential difference. Therefore, enhancers can be effective when used
with the products described herein. Further, changes in the flux due to
the drug concentration can also be evaluated. The activity coefficient
and the osmotic pressure changes depending upon the drug concentration,
and this greatly influence the speed of the ionic drug movement.

[0112]In addition to creating ions in the aqueous medium, it is also
possible to create ionic dissociation in polar matrixes and solvents. For
example, emulsion matrixes where water and oil are mixed using a
surfactant may also be applied, as well as a variety of polymers having
ether or ester bonding, and organic solvents and mixed organic and water
solvents having a dielectric constant of 20 or greater.

[0113]Specific ionizable active agents are described in more detail below.
As shown, these ionizable active agents can be delivered transdermally in
an ionized form (upon dissociation in an aqueous medium). In certain
embodiments, the transdermal delivery can be assisted in the presence of
an ionizable additive.

[0114]1. Procaterol HCl

[0115]Potentially adverse side effects may occur if more than 100 μg of
Procaterol is placed in a transdermal patch and that patch is mistakenly
ingested by a user or other individual. Also, medicinal efficacy and
safety considerations make it desirable that Procaterol be delivered at a
substantially constant rate. Development relating to transdermal delivery
patches using Procaterol HCl has been undertaken in the past, but a patch
has not yet been developed by others that is able to optimize both
factors, including the amount of drug in patch, and rate of delivery.
Thus, in various embodiments, the transdermal delivery device comprises
Procaterol HCl in the active agent layer, wherein at least 50%, or at
least 60%, or at least 75% or at least 90% of an initial amount (loading)
of Procaterol HCl is delivered over a period of 24 hours. Typically, for
safety concerns, the remaining Procaterol HCl after delivery should not
exceed 50% of the initial loading of Procaterol HCl.

[0116]To load Procaterol HCl on a transdermal delivery device (e.g., a
patch), an aqueous solution of Procaterol, or more preferably, a viscous
sol using hydroxypropyl cellulose (HPC) can be applied on top of a
polyethylene terephthalate (PET) film. Typically, no more than 100
micrograms of Procaterol can be loaded. The patch can be dried to remove
any water present during the loading process.

[0117]FIG. 9 shows a relationship between permeability rate of Procaterol
cations within the skin and the concentration of Procaterol HCl. FIG. 9
also shows the electric potential difference occurring within the skin
(measured by using the cell shown in FIG. 7). The electric potential
difference shown here is between the outside and the inside of the skin.
The "+/-" notation is opposite to that shown in Equation 12. FIG. 9 shows
results of measurements made using an aqueous solution of Procaterol HCl.
It is thought that the membrane potential may be generated due to the
influence of pH changes in solution. At 0.12 M, an electric potential
difference is present that tends to promote migration of cations in the
direction from the outside of the skin toward the inside due to an
electric field within the skin. At other concentrations, however, an
oppositely signed electric potential gradient occurs, which would tend to
hamper the movement of Procaterol cations into the skin. It is thought
that the electric potential differences develop due to the influence of
protons, Procaterol cations, and chloride ions.

[0118]The mobility of the Procaterol cations with respect to the mobility
of chloride ions can be obtained based on the results of the membrane
electrical potential measurement. It is noted that the mobilities of
Na.sup.+ and Cl.sup.- are nearly the same, as seen from results of
measuring the membrane potential using sodium chloride. Also, The
mobility of H.sup.+ is on the order of 1500 times higher than the
mobility of Cl.sup.-, based on the results of measuring the membrane
potential using HCl. These values have been used to make calculations.
Table 1 shows the results when using 0.12 M Procaterol HCl. Employing
values from the Table 1 that are the same as those measured, the ion
mobility of Procaterol ions becomes 0.13 with respect to that of chloride
ions. It can be seen that the migration speed of Procaterol ions is slow
compared to that of chloride ions.

[0120]Further, Table 3 shows experimental results of measurements made
using a Franz cell. Skin thickness and chloride ion mobility are
necessary to apply Eq. 11, and the chloride ion mobility was assumed to
be 1.5×10-13, and the skin thickness was assumed to be 0.01 cm
here. The mobility of the chloride ion is on the order of 1/10,000 of
that found in an aqueous solution. However, this assumption is thought to
be reasonable considering the results for solid polymer electrolytes.

[0121]Table 3 shows the actual amount of aqueous Procaterol delivered to
hairless mouse skin over time was measured using the Franz cell of FIG. 7
at a number of different concentrations (FIG. 10), as measured delivery
rates. The computed values are compared with the actual measured values
in FIG. 11. The trend between the two has good agreement, and it would
appear that flux values can be reliably predicted using Eq. 11
independently of any actual experimental measurements.

[0122]2. Sodium Diclofenac

[0123]High concentrations of sodium Diclofenac do not easily dissolve in
water, and it is thus customary to use a hydrophobic solvent. However,
many hydrophobic solvents are irritating to the skin, and therefore
cannot readily be used for a patch medication.

[0124]In certain embodiments, a transdermal delivery device including
sodium Diclofenac and an ionizable additive is capable of delivering
therapeutically effective amount of Diclofenac in an aqueous condition
(e.g., upon contacting skin and sweat on the skin). Sodium Diclofenac
dissociates into Diclofenac anions and sodium cations. The mobility of
Diclofenac anions was found by performing measurements of the membrane
potential of the skin. FIG. 12 shows a relationship between the
concentration of sodium Diclofenac and the delivery rate of Diclofenac
anions (diC.sup.-) to the skin. FIG. 13 shows the electric potential
difference generated within the skin. Results shown in Table 4 are
obtained for the mobility based on the data shown in FIGS. 12 and 13.

[0125]The mobility of Diclofenac anions was found to be 4.6 (compared to
that of chloride ions). This means that Diclofenac anions can be more
easily delivered to the skin than chloride ions. Further, computational
results shown in Table 5 can be obtained for the Diclofenac flux.

[0126]Table 6 shows measured results. FIG. 14 compares the measured
results with the computed (predicted) results. A correlation can be seen
between the computational results and the actual measured values. It is
thus possible to predict the delivery rate of Diclofenac ions using the
mobility obtained from measurement of the membrane potential.

[0127]The membrane potential shows negative values. Anions thus pass into
the skin while undergoing a deceleration. It follows that, by reducing
the potential difference occurring within the skin to zero, or making it
positive, it is possible to improve the delivery rate. One possible
method considered is to use KCl as an additive. KCl dissociates into
K.sup.+ and Cl.sup.- ions. From separate membrane potential measurements,
the mobility of K.sup.+ within the skin was found to be large compared to
that of Cl.sup.-. It is thus thought that KCl could be used to lower the
negative electric potential gradient occurring within the skin. 0.1% and
0.5% KCl was added to the Diclofenac solution and measurements of
membrane potential were performed, the results of which are shown in
Table 7.

[0128]The membrane potential difference indeed became smaller upon
addition of the KCl additive, which reduced the electric potential
gradient that tends to hinder delivery of Diclofenac into the skin. It
can be seen that the amount that the electric potential gradient is
reduced depends upon the amount of KCl added. In addition, it can also be
seen that a much greater flux was obtained with the sodium Diclofenac
solution containing the KCl additive compared to the solution without
KCl. The delivery rate of Diclofenac can thus be controlled by selecting
an appropriate additive to reduce the electric potential difference
occurring within the skin.

[0129]Diclofenac and 0.1% KCl can be used to manufacture a transdermal
patch by employing a sol similar to that used for Procaterol. Table 8
shows a comparison to three Diclofenac products currently on the market.
Our patch shows higher delivery.

[0130]Thus, a specific embodiment provides a transdermal delivery device
including in an active agent layer, Diclofenac and 0.1% KCl, and a sol
similar to that used for Procaterol. Table 8 shows a comparison to three
Diclofenac products currently on the market. The patch (F26) containing
ionizable additive KCl shows higher delivery.

[0132]Ascorbic acid is a two-glucoside conductor with high water
solubility. Hydrophobic ascorbic acid derivatives have been developed in
order to increase the skin permeation of ascorbic acid. However,
hydrophobic ascorbic acid derivatives may be combined with a hydrophobic
base in which a variety of additives may be used. This may lead to skin
irritation, and patches using such formulations may not be well accepted
by the public. It is thus described herein a topical formulation (e.g., a
hydrophilic lotion) having superior usability, without irritation,
without the use of additives by using ascorbic acid 2-glucoside.

[0133]Ascorbic acid 2-glucoside (AA2G) dissociates into AA2G- and H+ ions.
FIG. 15 shows a relationship between the concentration of AA2G and
AA2G-ions within the skin. FIG. 16 shows the electric potential
difference occurring within the skin. An electric potential difference
that tends to drive anions from outside of the skin toward the inside of
the skin occurs at concentrations of 0.06 M, 0.15 M, and 0.3 M. The
electric potential gradient weakens as the concentration becomes higher,
however, and it thus becomes more difficult to accelerate the diffusion
of AA2G- anions using this potential difference. The reason that the
potential difference is high at low concentration is thought to be due to
the influence of the ionic concentration difference between physiological
saline and AA2G within the skin. Further, different concentrations of
AA2G used leads to differences in the movement of H+ and AA2G- within the
skin. The electric potential difference found experimentally is thought
to occur due to the influence of AA2G- and H+.

[0134]It is possible to find the mobility of AA2G- (compared to that of
chloride ions) from the film potential, and Table 9 shows results for
AA2G at 0.3 M. From this table, the ratio between the mobility of AA2G-
and chloride ions is 0.83.

[0136]Table 11 shows experimental results for flux measurement. A
comparison between the computational results and the experimental results
is shown in FIG. 17. Both show a similar trend, and flux may thus be
predicted without doing any experiments by using Eq. 11.

[0138]Due to the low permeation rate of Lidocaine, is necessary to employ
a high concentration of Lidocaine HCl in order to achieve an anesthetic
effect. High concentrations of Lidocaine HCl, however, are irritating to
the skin. It is thus desirable to develop a patch capable of exhibiting a
sufficient anesthetizing effect by effectively delivering Lidocaine into
the skin. More specifically, concentrations of Lidocaine HCl that are
favorable for permeation can be established according the theoretical
model described herein.

[0139]Lidocaine HCl dissociates into Lidocaine cations (protonated
Lidocaine) and Cl- ions in water. A relationship between the
concentration of Lidocaine HCl and Lidocaine cations delivered within the
skin is shown in FIG. 18. FIG. 19 shows the electric potential difference
generated within the skin. An electric potential difference that does not
tend to drive Lidocaine ions into the skin is found at low concentration
(1%), but potential differences that tend to drive Lidocaine ions into
the skin occur at higher concentrations (e.g., 5% and 10%).

[0140]The mobility of Lidocaine cations with respect to chloride ions can
be found from the membrane potential results. Results for 5% Lidocaine
(185 mM) are shown in Table 12. Using a value from the table where the
membrane potential is the same as actual measurements, the mobility of
Lidocaine cations is 0.67 that of chloride ions. Lidocaine cations move
relatively slower than chloride ions.

[0142]Calculations were made assuming a skin thickness of 0.01 cm and a
chloride ion mobility of 1.5×10-13. FIG. 18 shows the
measurements of the actual amount of Lidocaine aqueous solution delivered
to hairless mouse skin over time at a variety of concentrations.

[0143]FIG. 20 shows a comparison of computed and actual experimental
values. Both show a similar trend, indicating that Eq. 11 can be used to
predict the amount of flux independently of performing experiments.

Topical Formulations

[0144]In certain embodiments, the active agent layer described in
connection with the transdermal delivery device can be hydrated to form
topical formulations. The topically formulation can be applied directly
and freely to the skin of a subject. Thus, certain embodiments provide a
topical formulation including a thickening agent and an ionized active
agent, as described herein, in combination with an aqueous medium,
wherein the topical formulation is substantially oil-free. The topical
formulations are typically formulated into spreadable forms (e.g.,
plasters and paste) according to known methods in the art. Various
additives, including permeation enhancers, antioxidants can be further
combined with the topical formulation.

[0145]In certain embodiments, the ionized active agent can be based on any
of the ionizable active agents described herein. One specific embodiment
provides a topical formulation comprising Procaterol cation (e.g.,
Procaterol HCl). For example, the topical formulation includes HPC,
Procaterol, urea, and water to provide an aqueous-based formulation.
Another specific embodiment provides a topical formulation comprising
Lidocaine cations (e.g., Lidocaine HCl). A further specific embodiment
provides a topical formulation comprising AA2G anion. A further specific
embodiment provides a topical formulation comprising Diclofenac anion
(e.g., sodium Diclofenac). As in the passive patch application, ionized
additives can be added to adjust the electrical potential difference.
Advantageously, the absence of oil in the topical formulation promotes
long-term stability of the ionized active agent in the topical
formulation.

[0146]The topical formulation can be formulated and used according to
known methods in the art.

Methods of Use and Making

[0147]The transdermal delivery device and topical formulations described
herein can be constructed by known methods in the art.

[0148]Typically, an active agent layer can be prepared by dispersing an
ionizable active agent in a viscous sol based on a thickening agent
(e.g., HPC). This was applied on top of a backing substrate, e.g.,
polyethylene terephthalate (PET) film. The backing substrate can be in
the shape of a patch, tape, disc, and so forth.

[0149]FIG. 21 shows an exemplary method 400 for manufacturing the delivery
devices 10a, 10b, and 10c, which hereinafter are collectively referred to
as delivery device 10. Various components, features, layers, etc. of the
delivery device 10 are referred to herein below by reference numerals,
which generally correspond to various components, features, layers of
delivery devices 10a, 10b, and 10c having the same reference numeral and
a letter appended thereto.

[0150]At 402, a backing substrate 12 is provided. The backing substrate 12
has a first surface 13 and an opposed second surface 125.

[0151]At 404, a base layer 14 having a thermoplastic resin is formed on
the first surface 13 of the backing substrate 12. In some embodiments,
the base layer 16 includes a poly(ethylene terephthalate) material

[0152]At 406, an active agent layer 16 is formed on the base layer 14 on
the first surface 13 of the backing substrate 12. The active agent layer
16 may include a thickening agent, a humectant, and a therapeutically
effective amount of a β2-adrenoreceptor agonist (or
β2-adrenoreceptor stimulant) or derivative or pharmaceutically
acceptable salt thereof.

[0153]In some embodiments, forming an active agent layer 16 on the base
layer 14 on the first surface of the backing substrate 12 includes
spin-coating a composition thereon. Compositions that may be spin-coated
include, but are not limited to: a composition having a thickening agent,
a humectant, and a therapeutically effective amount of an ionizable
active agent. For example, the active agent layer may comprise
hydroxypropyl cellulose, glycerol or urea, and Procaterol HCl or other
β2-adrenoreceptor agonist in various amounts such as an amount
ranging from about 0.1 wt % to about 5 wt % of the total composition.

[0154]At 408, which in some embodiments is optional, an active agent
replenishing layer 18 adjacent to the active agent layer 16 is formed.
The active agent replenishing layer 18 may be spin coated onto the active
agent layer and may include an ion exchange material and a sufficient
amount of the ionizable active agent (e.g., β2-adrenoreceptor
agonist) to maintain a weight percent composition of about 0.1 wt % to
about 5 wt % in the active agent layer 16.

[0155]FIGS. 22A-22C show a spin-coating process of a layer of material 600
according to one illustrated embodiment. In FIG. 22A, the layer of
material is disposed on a spinable disc 602 that is controllably driven
by rotation device 604. The rotation device 604 may rotate the disc 602
(and the layer of material 600 placed thereon) about an axis 606. In some
embodiments, the rotation device 602 is controllable/variable such that
the rate at which the disc 600 rotates is controllable.

[0156]In FIG. 22B, an amount of an active agent 608 is disposed, proximal
to the axis 606, on to the layer of material 600. In some embodiments,
the active agent 608 may be disposed on the layer of material 600 while
the disc 602 is rotating. In other embodiments, the active agent 608 may
disposed on the disc 602 while the disc 602 is not rotating, and then
rotation device 604 may be actuated to cause the disc to rotate.

[0157]In FIG. 22C, the active agent 608 is shown spread out over the layer
of material 600 in response to the rotation of the disc 602. Spin-coating
the active agent 608 onto the layer of material 600 provides an even
coating of the active agent 608 onto the layer of material 600. In some
embodiments, the layer of material 600 may be the base layer 14 without
the backing substrate 12, i.e., prior to the base layer 14 being applied
to the backing substrate 12. In other embodiments, the layer of material
600 may be the base layer 14 and the backing substrate 12.

[0158]Sol structures can be investigated by dynamic light scattering
(DLS). Scattered laser light can be used to identify the state of the HPC
contained in the sol. FIG. 23A shows a DLS measurement spectra plots. It
can be seen that different spectra are obtained for solutions containing
only HPC (b) versus solutions containing HPC, Procaterol, and glycerol
(a). HPC interacts with Procaterol and/or glycerol, forming aggregates.
Although it's important for the sol to contain aggregates in order to
maintain a certain level of viscosity, aggregates become an impediment to
ionic separation of Procaterol and/or release of Procaterol from the
patch. FIG. 23B shows a cross sectional view of an active agent layer
illustrating the interactions of HPC and Procaterol HCl according to one
illustrated embodiment.

[0159]The aggregate state between HPC and Procaterol becomes an important
factor in regulating the active agent sol in the patch. Procaterol HCl is
cationic, and HPC is highly hydrophilic. HPC may also be considered to
have anionic properties when its pH is acidic, thus leading to the
development of aggregates.

[0160]For a topical formulation, the ionizable active agent (e.g., AA2G)
can be formulated into lotions, cream, emulsions according to known
methods in the art.

[0161]The ionizable active agent described herein can thus be delivered
transdermally in a therapeutically effective amount for treatment of
various conditions. Certain embodiments describe method of treating a
condition associated with an obstructive respiratory ailment by applying
a transdermal delivery device to the skin of a subject, the transdermal
delivery device including an active agent layer comprising a
β-adrenoreceptor stimulant such as Procaterol HCl.

[0162]Obstructive respiratory ailments including, for example, asthma
(e.g., allergic asthma, bronchial asthma, and intrinsic asthma),
bronchoconstrictive disorders, chronic obstructive pulmonary disease, and
the like, affect millions of children and adults worldwide. These
ailments are typically characterized by bronchial hyper-responsiveness,
inflammation (e.g., airway inflammation), increased mucus production,
and/or intermittent airway obstruction, often in response to one or more
triggers or stresses. For example, obstructive respiratory ailments may
result from exposure to an environmental stimulant or allergen, air
pollutants, cold air, exercise or exertion, emotional stress, and the
like. In children, the most common triggers are viral illnesses such as
those that cause the common cold. Signs of an asthmatic episode include
wheezing, shortness of breath, chest tightness, coughing, rapid breathing
(tachypnea), prolonged expiration, a rapid heart rate (tachycardia),
rhonchous lung sounds, over-inflation of the chest, and the like.

[0163]Ionizable active agents belong to the class of amine-containing
β-adrenoreceptor stimulants can be formulated into an active agent
layer and delivered transdermally into a subject according to various
embodiments. β2-receptors are generally located on a number of
tissues including blood vessels, bronchi, gastro intestinal tract,
skeletal muscle, liver, and mast cell. Typically
β2-adrenoreceptor agonist act on the β2-adrenergic
receptor eliciting smooth muscle relaxation resulting in dilation of
bronchial passages (bronchodilation), relaxation of the gastro intestinal
tract, vasodilation in muscle and liver, relaxation of uterine muscle and
release of insulin, glycogenolysis in the liver, tremor in skeletal
muscle, inhibition of histamine release from mast cells, and the like.
β2-adrenoreceptor agonists are useful for treating asthma and
other related bronchospastic conditions, and the like. β-receptor
antagonists are also useful as anti-hypertensive agents.

[0164]Thus, one embodiment provides a method for treating a condition
associated with an obstructive respiratory ailment in a subject
comprising: applying to the subject's skin a passive transdermal delivery
device comprising: a backing substrate; and an active agent layer,
wherein the active agent layer is substantially anhydrous and oil-free
and includes a thickening agent and an ionizable active agent, and
wherein the ionizable active agent is electrically neutral in the active
agent layer and dissociates into an ionized active agent upon contacting
an aqueous medium; and allowing the ionizable active agent to dissociate
into the ionized active agent.

[0165]In certain embodiments, the method comprises contacting the
ionizable active agent to sweat of the subject's skin to produce the
ionized active agent.

[0166]In other embodiments, the ionizable active agent is a
β-receptor antagonist. In a specific embodiment, the ionizable
active agent is Procaterol HCl.

[0167]In some embodiments, at least 50% of the Procaterol HCl is delivered
through the skin of the subject within a 24 hour period.

[0169]At 660, a transdermal delivery device comprising from about 25 μg
to about 100 μg of an active agent having β-adrenoreceptor
stimulant activity is applied to a biological interface of a subject. A
skill artisan can select an appropriate amount of an active agent,
however, based on the condition to be treated or the pharmacokinetics, or
other criteria or properties of the active agent to achieve the desired
effect (e.g., an amount sufficient to alleviate the condition associated
with an obstructive respiratory ailment).

[0170]At 670, the active agent having β-adrenoreceptor stimulant
activity is delivered to the biological interface in an amount sufficient
to alleviate the condition associated with an obstructive respiratory
ailment.

[0171]In some embodiments, transdermally delivering the active agent
having β-adrenoreceptor stimulant activity to the biological
interface includes transferring a therapeutically effective amount of a
β2-adrenoreceptor agonist to the biological interface of the
subjected via diffusion. In some embodiments, transdermally delivering
the active agent having β-adrenoreceptor stimulant activity to the
biological interface includes transferring a therapeutically effective
amount of a β2-adrenoreceptor agonist selected from Procaterol
HCl, Procaterol HCl hemihydrate, or a derivative or pharmaceutically
acceptable salt thereof to the biological interface of the subjected.

[0172]In the description above, active agents such as ionic exchange
materials were described as being disposed on a patch for being applied
to the skin of a subject. In alternative embodiments, active agents
including, but not limited to, ion exchange materials may be in the form
of a powder or cream that may be applied to the skin of a subject.

[0173]The various embodiments described herein are further illustrated by
the following non-limiting examples.

EXAMPLES

[0174]1. In-Vitro Permeation Testing

[0175]Delivery devices 10a, 10b, and 10c, which are hereinafter
collectively referred to as delivery device 10, may be tested using both
in vitro and in vivo. In vitro testing may be performed using a passive
diffusion-testing device such as a Kelder cell or a Franz cell, among
other types of testing devices. FIGS. 25A, 25B, and 25C show multiple
exemplary passive diffusion measuring devices 750 used for testing a
delivery device 10.

[0176]The passive diffusion measuring device 750 includes a first end
plate 752 and a second end plate 754. A plurality of coupling features
such as holes 756 are formed on the first end plate 752. The second end
plate 754 includes a number of coupling features such as arms 758, which
are complementarily aligned with the holes 756. The holes 756 are sized
and shaped to receive at least a portion of the arms 758. In operable
position, a portion of the arms 758 extend through the holes 756, and the
arms 758 receive fasteners 760, which hold the arms in place.

[0177]Sandwiched between the first end plate 752 and the second end plate
754 is a first cap 762, the delivery device 10, a permeable membrane 764,
a reservoir 766, and a second cap 768. The first cap 762 abuts the first
end plate 752, and the second cap 768 abuts the second end plate 754. The
first cap 762 and the second cap 768 may be non-permeable and made from a
material such as silicon rubber.

[0179]Interposing the permeable membrane 764 and the second cap 768 is the
reservoir 766. The reservoir 766 is made from a non-permeable material
such as rubber, silicon rubber, glass, and the like. The reservoir 766
may be generally cylindrical with an open end 770 that is in fluidic
communication with a generally hollow interior 772. The open end 770
abuts the permeable membrane 764. A fluid 774 such as Phosphate Buffered
Saline (PBS) is disposed in the hollow interior 772. At the open end 770,
the fluid 774 contacts the permeable membrane 764. The active agent in
the delivery device diffuses through the permeable membrane 764 in to the
fluid 774. In the experiments described below, the reservoir 766 may hold
about 4 milliliters of the fluid 774.

[0180]2. In-Vitro Testing Conditions and Measurements

[0181]Typically, 17 ml of phosphate buffered saline (PBS, sold by Wako
Pure Chemical Industries) was injected into the receptor cell, and a 10
mm stirring bar was used to agitate the solution during the test. The
Franz cell was placed in an incubator (made by ESPEC, model LH-113) with
the temperature set to 32° C. and the humidity set to 70%. Samples
were typically extracted from the cell at predetermined times using a 200
μl Gilson Pipetman. 200 μl of PBS was then added to the cell after
each sampling operation.

[0182]For measuring the active agent (e.g., Procaterol cation) permeated,
a standard solution with known concentration can be prepared and compared
with the concentration measured. Using Procaterol HCl as an example, 50
mg of Procaterol HCl (97.25% anhydrous) was accurately measured out, and
then added to water to form 50 ml of solution ("Procaterol concentrate
liquid"). The standard concentrate was then diluted ("Procaterol standard
solution") and used as a mobile phase for high performance (or pressure)
liquid chromatography (HPLC). The Procaterol concentrate liquid was
sealed in a light shielding bottle and stored in a refrigerator. 10 μl
of each test sample and 10 μl of the standard solution was measured
using HPLC, and Procaterol peak areas At (test samples) and As
(standard solution) were determined for each sample. Procaterol HCl
masses were then found for each test sample using the following equation:

[0183]Amount of Procaterol HCl in test solution (g/μl)=amount of
anhydrous Procaterol in standard concentrate
liquid×At/As×1.0276, where 1.0276 is the ratio
between the molecular weight of 1/2 hydrated Procaterol HCl/the molecular
weight of anhydrous Procaterol HCl=335.83/326.82

[0184]Below are an exemplary condition and instrument for measuring the
concentration of Procaterol cations permeated:

[0203]In Example 1, before testing the delivery device 10, sixteen tests
were performed at four different agent concentrations (four tests (#1,
#2, #3, and #4) for each concentration of active agent) using Procaterol
HCl in order to investigate the transport of Procaterol cation into and
through skin along a concentration gradient. A Franz cell was used at
32° C. using hairless mouse skin as a permeable membrane. 720
corresponds to the average delivery of a 5 wt % Procaterol-HCl
concentration, 722 corresponds to the average delivery of a 2.5 wt %
Procaterol-HCl concentration, 724 corresponds to the average delivery of
a 1 wt % Procaterol-HCl concentration, and 726 corresponds to the average
delivery of a 0.5 wt % Procaterol-HCl concentration. FIG. 26 shows the
average amount of active agent delivered to the reservoir 772, which has
PBS fluid 74 therein, versus time for the four agent concentrations 720,
722, 724, and 726. It can be seen that the amount of Procaterol delivered
through the skin increases over time. Further, it can also be seen that
the amount of Procaterol delivered increases with increased Procaterol
concentration. To deliver a medically effective amount of Procaterol
through the skin, the concentration of the Procaterol solution must be
equal to or greater than a certain threshold concentration. A sufficient
amount of Procaterol dissolved in water was used in this experiment, thus
leading to a rather large Procaterol delivery speed. It is therefore
possible to deliver Procaterol through the skin, provided that the
solution exists in proximity to the surface of the skin. Table 16 shows
the details of the test delivery devices 720-726.

[0204]It is generally possible to manufacture a transdermal delivery patch
using a hydrophilic gel polymer matrix such as polyvinyl pyrrolidone or
polyvinyl alcohol. Procaterol is a hydrophilic active agent, however, and
thus smooth release from within a polymer matrix may not always be
possible.

[0205]FIGS. 27-32 show in vitro test results for various embodiments of
the delivery device 10 under various test conditions and for various
concentrations of agents.

[0206]Examples 2-7 described below generally employed a high viscosity sol
solution in order to hold Procaterol. Several wt % of hydroxypropyl
cellulose (HPC) was dissolved in water in order to form an active agent
containing sol. Procaterol HCl was then dissolved in the sol. The sol was
applied to a PET sheet, forming a patch. Glycerol (generally 10 wt %) was
added to, among other things, promote delivery. The amount of active
agent solution applied to the PET contained approximately 20
μg/cm2 of Procaterol. In some tests, a composition of HPC and
glycerol was made and allowed to repose for a given period of time, such
as a day or two. In some situations, the period of repose may be shorter
or longer.

[0207]Patches were applied to the skin (frozen or raw) of a hairless
mouse, and the amount of Procaterol delivered was measured using the
previously described Frantz cell setup, with the patch replacing the
solution. Experiments 2-7 show that the amount of Procaterol on the donor
side increases over time, and passes through the skin. Although Examples
2-7 can measure the amount of Procaterol delivered through the skin, the
actual delivery mechanism of Procaterol may be complex.

Example 2

[0208]One lot of six delivery devices was prepared according to the
embodiment shown in FIG. 4A-4B. The surface area for each respective
active agent layer 16 was approximately 1.12 cm2. In Example 2,
three of the delivery devices were tested in the passive diffusion
measuring device 750 (FIG. 25A), and frozen skin was used for the
permeable membrane 764. Each respective active agent layer 16 included
HPC (approximately 1 wt %) and Procaterol-HCl (approximately 1 wt %);
each respective replenishing layer 18 included HPC (approximately 1 wt
%). FIG. 27 shows the amount of active agent delivered to the reservoir
772, which has PBS fluid 774 therein, versus time for three delivery
devices, individually referenced as test devices 101, 102, and 103. Table
16A shows flux rate measured for the test devices 101, 102, and 103,
calculated using data taken at 11.5 hours. Three further test devices
from the one lot, individually referenced as test devices 104, 105, and
106, were analyzed to determine the amount of active agent present in
each device. Table 16B shows active agent amount and concentration
details for the delivery devices 104, 105, and 106.

[0209]In Example 3, one lot of eight delivery devices was prepared
according to the embodiment shown in FIGS. 1-2B. The surface area for
each respective active agent layer 16 was approximately 1.12 cm2. In
Example 3, the delivery devices were tested in the passive diffusion
measuring device 750 (FIG. 25A), and raw skin was used for the permeable
membrane 764. Each respective active agent layer 16 included HPC
(approximately 1 wt %) and Procaterol-HCl (approximately 1 wt %). FIG. 28
shows the amount of active agent delivered to the reservoir 772, which
has PBS fluid 774 therein, versus time for five delivery devices,
individually referenced as test delivery devices 201, 202, 203, 204, and
205. Table 17A shows flux rate measured for the test devices 201, 202,
203, 204, and 205, calculated using data taken at 12.0 hours. Three
further test devices from the one lot, individually referenced as test
devices 206, 207, and 208, were analyzed to determine the amount of
active agent present in each device. Table 17B shows active agent amount
and concentration details for the delivery devices 206, 207, and 208.

[0210]In Example 4, one lot of ten delivery devices was prepared according
to the embodiment shown in FIGS. 1-2B. The surface area for each
respective active agent layer 16 was approximately 1.12 cm2. In
Example 4, the delivery devices were tested in the passive diffusion
measuring device 750 (FIG. 25A), and raw skin was used for the permeable
membrane 764. Each respective active agent layer 16 included glycerol
(approximately 10 wt %), HPC (approximately 0.5 wt %) and Procaterol-HCl
(approximately 2.5 wt %). FIG. 29 shows the amount of active agent
delivered to the reservoir 772, which has PBS fluid 774 therein, versus
time for five delivery devices, individually referenced as devices 301,
302, 303, 304, and 305. Table 18A shows flux rate measured for the test
devices 301-305, calculated using data taken at 12.0 hours. Five further
test devices from the one lot, individually referenced as test devices
306-310, were analyzed to determine the amount of active agent present in
each device. Table 18B shows active agent amount and concentration
details for the delivery devices 306-310.

[0211]In Example 5, eighteen delivery devices were prepared according to
the embodiment shown in FIGS. 1-2B. The surface area for each respective
active agent layer 16 was approximately 1.12 cm2. In Example 5, the
delivery devices were tested in the passive diffusion measuring device
750 (FIG. 25A), and frozen skin was used for the permeable membrane 764.
Each respective active agent layer 16 included glycerol (approximately 10
wt %), HPC (approximately 0.5 wt %) Procaterol-HCl (approximately 2.5 wt
%), and a buffer solution. Three different pH value buffer solutions were
used. FIG. 30 shows the amount of active agent delivered to the reservoir
772, which has PBS fluid 774 therein, versus time for nine delivery
devices, individually referenced as devices 401-409. Table 19A shows flux
rate measured for the test devices 401, 402, and 403, which used a pH 4.0
buffer solution. The flux rates were calculated using data taken at 8.0
hours. Table 19B shows flux rate measured for the test devices 404, 405,
and 406, which used a pH 5.0 buffer solution. The flux rates were
calculated using data taken at 8.0 hours. Table 19C shows flux rate
measured for the test devices 407, 408, and 409, which used a pH 6.0
buffer solution. The flux rates were calculated using data taken at 8.0
hours. Nine further test devices from the one lot, individually
referenced as test devices 410-418, were analyzed to determine the amount
of active agent present in each device. Table 19D shows the details of
the active agent amount and concentration for the delivery devices 410,
411, and 412, which used the pH 4.0 buffer solution. Table 19E shows
active agent amount and concentration details for the delivery devices
413, 414, and 415, which used the pH buffer 5.0 solution. Table 19F shows
active agent amount and concentration details for the delivery devices
416, 417, and 418, which used the pH buffer 6.0 solution.

[0212]In Example 6, fourteen delivery devices were prepared according to
the embodiment shown in FIGS. 1-2B. The surface area for each respective
active agent layer 16 was approximately 1.12 cm2. In experiment 6,
the delivery devices were tested in the passive diffusion measuring
device 750 (FIG. 25A), and raw skin was used for the permeable membrane
764. Each respective active agent layer 16 included glycerol
(approximately 10 wt %), HPC (approximately 0.5 wt %) Procaterol-HCl
(approximately 2.5 wt %), and a buffer solution. Two different pH buffer
solutions were used. FIG. 31 shows the amount of active agent delivered
to the reservoir 772, which has PBS fluid 774 therein, versus time for
six delivery devices, individually referenced as devices 501-506. Table
20A shows flux rate measured for the test devices 501, 502, and 503,
which used a pH 4.0 buffer solution. The flux rates were calculated using
data taken at 8.0 hours. Table 20B shows flux rate measured for the test
devices 504, 505, and 506, which used a pH 5.0 buffer solution. The flux
rates were calculated using data taken at 8.0 hours. Eight further test
devices from the one lot, individually referenced as test devices
507-514, were analyzed to determine the amount of active agent present in
each device. Table 20C shows active agent amount and concentration
details for the delivery devices 507-510, which used the pH 4.0 buffer
solution. Table 20D shows active agent amount and concentration details
for the delivery devices 511-514, which used the pH buffer 5.0 solution.

[0213]In Example 7, eight delivery devices were prepared according to the
embodiment shown in FIGS. 1-2B. The surface area for each respective
active agent layer 16 was approximately 1.12 cm2. In Example 7, the
delivery devices were tested in a Franz cell, and raw skin was used for a
permeable membrane. Each respective active agent layer 16 included
glycerol (approximately 10 wt %), HPC (approximately 0.5 wt %), and
Procaterol-HCl (approximately 2.5 wt %). FIG. 32 shows the amount of
active agent delivered to the reservoir 772, which has PBS fluid 774
therein, versus time for four delivery devices, individually referenced
as devices 601-604. Table 21A shows flux rate measured for the test
devices 601-604, calculated using data taken at 12.0 hours. Four further
test devices from the one lot, individually referenced as test devices
605-608, were analyzed to determine the amount of active agent present in
each device. Table 21B shows active agent amount and concentration
details for the delivery devices 605-608.